Trial to Test the Effects of Adding 1 of 2 New Treatment Agents to Commonly Used Chemotherapy Combinations

Brief description of study

The AML18 Trial will evaluate several relevant therapeutic questions in Acute Myeloid
Leukaemia (AML), as defined by the WHO, and High Risk Myelodysplastic Syndrome. The trial is
primarily designed for patients over 60 years considered fit for an intensive
chemotherapeutic approach, but younger patients who may not be considered suitable for the
concurrent NCRI AML Trial for younger patients may also enter. Patients for whom intensive
chemotherapy is not thought suitable may enter the concurrent NCRI trial of less intensive
therapy (LI1). Approximately 1600 patients will be recruited.

At entry, a randomisation will compare a standard chemotherapy schedule DA
(Daunorubicin/Ara-C) combined with 1 dose of Mylotarg (gemtuzumab ozogamicin, or GO) in
course 1 against CPX-351. Patients who have known adverse risk cytogenetics (using Grimwade
2010 classification favourable/intermediate/adverse) at diagnosis may enter a Phase 2
evaluation of the combination of Vosaroxin plus Decitabine. Patients who achieve complete
remission (CR) and who are MRD negative by flow cytometry after course one of DA will receive
one further course of DA, with a randomisation to receive, either a course of DA or
intermediate dose Cytarabine (IDAC) as a third course. Patients who are MRD negative by flow
cytometry after course one of CPX-351 will receive up to 2 further course of CPX. Patients
who fail to achieve a CR after course 1 of DA or who are MRD positive by flow cytometry or
for whom MRD information is not available, are eligible to be randomised to compare DA with
DA plus Cladribine (DAC) or FLAG-Ida for up to two courses of therapy. Patients who fail to
achieve a CR after course 1 of CPX-351 or who are MRD positive by flow cytometry or for whom
MRD information is not available are eligible to be randomised between a second course of
standard dose CPX versus a repeat of the course 1 schedule. Patients receiving Vosaroxin and
Decitabine are excluded from these post course 1 randomisations .

Following the outcome of course 1, patients who received DA chemotherapy on course 1 will be
randomised to receive further chemotherapy with the 2nd generation FLT3 inhibitor AC220.
Patients randomised to AC220 will be allocated a maximum of 3 courses (short AC220) or 3
courses plus maintenance for 1 year (long AC220). Patients receiving Vosaroxin and Decitabine
are excluded from this randomisation.

Patients will be eligible for a non-intensive allogeneic stem cell transplant if a suitable
HLA matched donor is available.

Detailed Study Description

AML18 is a trial primarily for older patients with AML and high risk Myelodysplastic Syndrome
(MDS). It offers a randomised controlled Phase II/III trial which uses a factorial design for
maximum efficiency to evaluate two induction options followed by treatment with small
molecule beyond course 1, and dose intensification for patients without evidence of MRD
negativity.

There are five randomised comparisons within the trial:

At diagnosis:

For patients not known to have adverse risk cytogenetics DA chemotherapy plus a single
dose of 3 mg/m2 of Mylotarg versus CPX-351. Patients with abnormal LFTs can enter the
randomisation but receive DA alone or CPX-351.

2. For patients who received DA chemotherapy but are not in CR or who are MRD +ve, or for
whom MRD is not assessable.

DA versus DAC versus FLAG-Ida

3. All patients at second course who have received DA and have not received Vosaroxin and
Decitabine induction AC220 versus no AC220 for a maximum of 3 cycles; then with or
without maintenance for 1 year for patients allocated AC220

4. For patients who are in CR or CRi and MRD -ve post course1 and have completed 2 courses
of DA DA versus intermediate dose Cytarabine (IDAC)

5. For patients who received CPX-351 chemotherapy but are not in CR or who are MRD +ve, or
for whom MRD is not assessable CPX-351 100 units/m2 x 3 doses versus CPX-351 100
units/m2 x 2 doses